The long-term objectives of the proposed research program are: (1) a classification of developmental disease of the nervous system based upon pathologic specimens in terms of cellular and subcellular structure. As is true with the growth rings and branch arbors of trees, the developmental history of neurons should be reflected in their patterns of growth and differentiation. Our research involves the analysis of cellular abnormalities in cortical structures of human pathologic specimens and the reeler mutant mouse. Research in the reeler mutant mouse is concerned with the morphogenetic events through which relative cell position is achieved in cortical structures, as well as the morphologic consequences of cell malposition. An organizing theme has been an inquiry into neural systems organization, the interaction of individual cells withother cellular elements, under normal and pathologic circumstances. The immediate goal in human studies has been to extract from cellular abnormalities observed in cortical structures in Golgi and electron microscopic, as well as routine histologic preparations, information about the mechanisms of pathologic process and their time of action. To date, this approach has revealed a number of qualitative abnormalities in cell form which have provided important new insights in the pathophysiology of certain of the human cerebral malformations and inborn errors of metabolism. However, in many specimens, abnormalities in the geometric form of cortical neurons are not apparent, or are confined to subtle alterations in the size or relative numbers of various subclasses of neural structures. It is likely that significant abnormalities exist, but are beyond the resolution of crude qualitative methodologies. We propose to strike radically at these conceptual and methodologic impasses by developing computer-assisted microscopic techniques for the quantitative analysis of the various parameters of neuronal form, both in the normal cortex, and in cortex from pathologic specimens of the developmental epoch.